A Genetic Analysis of the Caenorhabditis elegans Detoxification Response. Issue 2 (1st June 2017)

• Record Type: Journal Article
• Authors: Fukushige, Tetsunari; Smith, Harold E; Miwa, Johji; Krause, Michael W; Hanover, John A
• Is Part Of: Genetics. Volume 206:Issue 2(2017)
• Page Start: 939
• Page End: 952
• Publication Date: 2017-06-01
• Subjects: C. elegans -- stress response -- detoxification -- XREP; Genetics -- Periodicals; 576.5
• DOI: 10.1534/genetics.117.202515
• Languages: English
• ISSNs: 0016-6731

Abstract

Abstract: Oxidative damage contributes to human diseases of aging including diabetes, cancer, and cardiovascular disorders. Reactive oxygen species resulting from xenobiotic and endogenous metabolites are sensed by a poorly understood process, triggering a cascade of regulatory factors and leading to the activation of the transcription factor Nrf2 (Nuclear factor-erythroid-related factor 2, SKN-1 in Caenorhabditis elegans ). Nrf2/SKN-1 activation promotes the induction of the phase II detoxification system that serves to limit oxidative stress. We have extended a previous C. elegans genetic approach to explore the mechanisms by which a phase II enzyme is induced by endogenous and exogenous oxidants. The xrep ( xenobiotics response pathway ) mutants were isolated as defective in their ability to properly regulate the induction of a glutathione S -transferase (GST) reporter. The xrep-1 gene was previously identified as wdr-23, which encodes a C. elegans homolog of the mammalian β-propeller repeat-containing protein WDR-23 . Here, we identify and confirm the mutations in xrep-2, xrep-3, and xrep-4 . The xrep-2 gene is alh-6, an ortholog of a human gene mutated in familial hyperprolinemia. The xrep-3 mutation is a gain-of-function allele of skn-1 . The xrep-4 gene is F46F11.6, which encodes a F-box-containing protein. We demonstrate that xrep-4 alters the stability of WDR-23 ( xrep-1 ), a key regulator of SKN-1 ( xrep-3 ). Epistatic relationships among the xrep mutants and their interacting partners allow us to propose an ordered genetic pathway by which endogenous and exogenous stressors induce the phase II detoxification response.